Parasitic diseases, in particular those caused by protozoa (such as malaria, pathogens: plasmodia), or by trematodes (such as schistosomiasis, for example urinary schistosomiasis, caused by schistosomes, as Schistosoma haematobium), constitute a substantial proportion of the diseases, especially in developing countries. Malaria, transmitted by the Anopheles mosquito and caused by protozoa of the Plasmodium genus, is a disease which occurs in about 100 million people each year, of whom around one million die. A distinction is drawn between Malaria tropica (caused by Plasmodium falciparum), Malaria tertiana (caused by Plasmodium vivax or Plasmodium ovale) and Malaria quartana (caused by Plasmodium malariae). Malaria tropica is the most severe form of the disease.
Benflumetol (also lumefantrine), a compound of formula ##STR2##
is a compound which, in combination with artemether (see EP 0 500 823)--a sesquiterpene lactone derivative of the naturally occurring substance artemisinin with the name [3R-(3.alpha., 5.alpha..beta., 6.beta., 8.alpha..beta., 9.alpha., 10.alpha., 12.beta.,-12aR)]-decahydro-10-methoxy-3,6,9-trimethyl-3,12epoxy-12H-pyrano [4,3j]-1,2-benzodioxepin, is in the review stage for approval worldwide as a treatment for malaria.
Because of phenomena such as the development of resistance, it remains an urgent necessity to find new compounds which show particularly good efficacy against malaria and minimal toxicity.
The different half-lives of the substances which are active against malaria also mean that further compounds should be made available which show a pharmacokinetic behaviour distinct from the antimalarial substances already established. Chloroquine, for example, has a very long half-life, artemether a relatively short half-life (2 hours in plasma), and benflumetol for example has a plasma half-life of 4-6 days in patients.
The solubility of benflumetol is also not very good, and when it is taken for example with foods having a high fat content the absorption can be up to 16 times higher than it is in the absence of such fatty foods, so that dosing cannot be optimally controlled.
Surprisingly, a new class of compounds has now been found which have a number of beneficial properties, meet one or more of the above requirements in particular, and facilitate for example the treatment of severe cases of malaria or a corresponding prophylaxis, or in the broader sense of schistosomiasis, the prevention or treatment of potentially multiresistant malaria, and new pharmaceutical formulations, and thus an improved pharmacokinetics, but in particular show especially good efficacy against plasmodia.